5月3日，国际期刊Oncogene 在线发表了中国科学院上海生命科学研究院/上海交通大学医学院健康科学研究所时玉舫研究组题为Tumour cell-derived exosomes endow mesenchymal stromal cells with tumour-promotion capabilities 的研究成果，阐述了肿瘤细胞的分泌囊泡在诱导间充质干细胞促肿瘤生长方面的重要作用以及相关机制。

间充质干细胞具有向肿瘤趋化的特性，已经被证实可以通过分泌生长因子、趋化因子和表达免疫调节因子等，促进血管生成，调节肿瘤免疫微环境，影响肿瘤生长。时玉舫研究组在前期研究中已发现，相比骨髓间充质干细胞，肿瘤间充质干细胞具有显著地促进肿瘤生长的作用。这些肿瘤间充质干细胞通过分泌大量的趋化因子（CCL-2，CCL-7，CCL-12），招募单核细胞、巨噬细胞在肿瘤部位的聚集，塑造肿瘤免疫抑制环境，促进肿瘤生长。肿瘤间充质干细胞的这些特征的获得与肿瘤微环境存在密切联系。同时，肿瘤间充质干细胞可以进一步“同化”新到达肿瘤部位的骨髓间充质干细胞，使其具有与肿瘤间充质干细胞相似的特征，并获得促进肿瘤生长的能力。然而，肿瘤间充质干细胞的初始形成过程以及相关的参与因素，仍缺乏相关的研究。

博士研究生杜黎明和林良宇在研究员时玉舫和王莹的指导下发现，肿瘤在发生发展过程中，会产生大量的囊泡（exosomes），这些囊泡可以被间充质干细胞摄取，调控间充质干细胞中趋化因子（CCL-2，CCL-7，CCL-12）的表达。相比于正常的间充质干细胞，肿瘤囊泡处理过的间充质干细胞能够招募更多的巨噬细胞向肿瘤部位迁移，促进肿瘤免疫抑制环境形成，促进肿瘤的生长。当阻断巨噬细胞的迁移或者除去实验小鼠体内的巨噬细胞后，肿瘤囊泡处理过的间充质干细胞的促肿瘤能力大大减低。这一发现表明，肿瘤细胞所产生的囊泡在诱导正常组织间充质干细胞向促肿瘤间充质干细胞演化中起到了重要的作用，对揭示肿瘤中间充质干细胞的来源具有重要意义。同时，这一成果为了解肿瘤细胞、间充质干细胞及免疫细胞之间的交互调控在肿瘤中的作用提供了新的视角和机制。

该工作得到了科技部、国家自然科学基金委、中国科学院和上海市科委的相关资助。

原文摘要：

Tumour cell-derived exosomes endow mesenchymal stromal cells with tumour-promotion capabilities

Mesenchymal stromal cells (MSCs) are a major component of the tumour microenvironment. A plethora of elegant studies focusing on tumour-derived MSCs have shown that they, unlike normal MSCs in other tissue, exhibit a strong ability to promote tumour progression. However, the mechanisms underlying the conversion of normal MSCs into tumour-associated MSCs are unknown. We report here a critical role of tumour cell-derived exosomes in endowing bone marrow-derived MSCs (BM-MSCs) with a tumour-favourable phenotype. Tumour cell-derived exosomes affected neither the growth factor production nor the immunosuppressive property of MSCs; rather, they endowed MSCs with a strong ability to promote macrophage infiltration into B16-F0 melanoma or EL-4 lymphoma. Ablation of macrophages by clodronate liposome administration reversed the tumour-promoting effect of MSCs educated by tumour cell-derived exosomes (TE-MSCs) on the tumour growth. By comparing the chemokine profile of BM-MSCs with that of TE-MSCs, we found that TE-MSCs produced a large amount of CCR2 ligands, CCL2 and CCL7, which are responsible for macrophage recruitment. CCR2-specific inhibitor was found to block the tumour-promoting effect of TE-MSCs. Thus, our investigations demonstrated that tumour cell-derived exosomes confer BM-MSCs the ability to enhance tumour growth. Therefore, we uncovered a novel mechanism underlying the conversion of normal MSCs to tumour-associated MSCs.